This project seeks to improve the clinical care available to patients with disorders of ovarian follicle function and ovulation through research using animal models as well as clinical protocols. In pursuing this goal, we expect to expand understanding of the ovarian follicle in health and disease. We have focused on premature ovarian failure, a condition that prematurely terminates ovarian function and fertility in 1% of women. We have particular interest in autoimmunity as a cause of ovarian failure. In a mouse model, we found that autoantibodies from mice with experimental autoimmune oophoritis bind to a 120 kd protein that is specific to the oocyte cytoplasm. Using this immune serum we identified a novel oocyte-specific gene that may represent the inciting antigen in this disease. In the clinic, we have found that premature ovarian failure is not merely a premature menopause. One half of these young women have ovaries that function intermittently. We successfully treated one woman with histologically proven autoimmune oophoritis under an approved research protocol using low dose prednisone. We have also demonstrated that inappropriate luteinization of graafian follicles is a major pathophysiologic mechanism preventing normal follicle function. We plan to develop therapeutic strategies to prevent this inappropriate luteinization and possibly restore fertility to some of these young women. In a related effort, we are investigating the physiology of the luteinization process in normal fertile women. We are also investigating other adverse health consequences of premature ovarian failure. We found that these young women have deficient circulating free testosterone levels, and, surprisingly, we found that two thirds of our patients have a reduced bone density that may place them at increased risk of hip fracture. Furthermore, we have preliminary findings to suggest that one-third of these young women may have an associated mineralocorticoid deficiency. Premature ovarian failure is clearly a more complex condition than has been previously recognized. We have clinical studies underway to develop hormone replacement methods appropriate specifically to these young women. We have also expanded our efforts to include clinical studies of polycystic ovary syndrome.